Cerebral microbleeds and vascular cognitive impairment
Introduction
Vascular cognitive impairment (VCI) is a key healthcare challenge facing all aging Western societies, second only to Alzheimer's Disease (AD) as a cause of dementia [1]. Initial concepts of VCI invoked cortical or subcortical infarction ā leading to the terms āmulti-infarct dementiaā and āpost-stroke dementiaā. However subcortical small vessel disease (often not causing acute or overt clinical symptoms) also plays a critical role in VCI [2], [3], [4]. MRI is the most important tool for detecting and quantifying small vessel diseases, and forms part of current diagnostic criteria for vascular dementia [1]. MRI manifestations of small vessel diseases including white matter hyperintensities (WMH: bright signal areas on T2-weighted or FLAIR images including leukoaraiosis) and lacunes have been recognized for many years. Cerebral microbleeds (CMBs) ā small, perviascular haemorrhages seen as well-demarcated, rounded lesions on MRI sequences sensitive to magnetic susceptibility ā are also now recognized as a manifestation of small vessel pathology [5] (Fig.Ā 1), but their clinical impact on cognition remains uncertain [6]. This review will consider how CMBs may be relevant in the study of VCI.
White matter lesions (WML), also termed white matter changes, white matter hyperintensities, or leukoaraiosis, appear on T2-weighted MRI sequences as regions of high signal in the periventricular or subcortical white matter. WML appear on CT as areas of relative hypoattenuation in the same regions. The pathological correlates of WML include myelin loss, gliosis, axonal loss, microinfarction and dilation of perivascular spaces. [7] The precise pathogenesis of WML is unknown, but there is substantial evidence that they are related to vascular disease; one hypothesis is that WML are related to chronic hypoperfusion in the territory of small perforating arteries, a proposal supported by neuroimaging evidence of hypoperfusion within white matter regions [8], [9]. Epidemiologic studies show strong relationships between WML and vascular risk factors, ischemic stroke and intracerebral hemorrhage. Furthermore it is clear that small vessel arterial disease can itself cause WML, as patients with the hereditary vascular diseases CADASIL and familial CAA present with extensive WML at a relatively early age, when conventional risk factors and ageing are unlikely to make a major contribution. Correlations of WMH with cognition have often been modest, particularly in patients with symptomatic cerebrovascular disease [10], [11]. The limited correlations in some studies may be a reflection of both the pathological heterogeneity of small vessel diseases, and the lack of pathological specificity of conventional MRI, whose signal is largely related to the local concentration of water protons. Tissue water content may be affected by many pathological processes including infarction, ischaemic demyelination and gliosis, which may have different functional effects. There is thus a need for a better understanding of the pathological basis of MRI changes, and for more specific imaging markers to detect and quantify small vessel pathology.
Another reason that previous correlations of MRI changes and cognition have been limited is that VCI and AD have generally been considered as separate, non-overlapping entities. This dichotomy is an oversimplification, since both VCI and AD are diseases of older people and commonly co-exist. Furthermore, vascular and degenerative processes have complex interactions and, potentially, synergistic deleterious effects on brain function. For example, hypertension is a risk factor for developing AD, and WMH are commonly found on the MRI scans of people with AD [12]. It has also been hypothesized that pre-existing AD pathology may make people with stroke more vulnerable to post-stroke cognitive decline [13]. However, exactly how these pathologies are linked remains a critical question in understanding mechanisms of dementia. A key question is whether AD and cerebrovascular disease simply co-exist in some individuals, or do these pathological processes interact? One intriguing process that may link cerebrovascular disease with AD is cerebral amyloid angiopathy (CAA). CAA is characterized by amyloid deposition (principally in cortical and leptomeningeal small vessels), and is common with advancing age and in AD, as well as being an important cause of spontaneous intracerebral haemorrhage in older individuals [14]. One possibility is that vascular amyloid adversely affects vessel reactivity and small vessel function, causing ischaemic damage (white matter ischaemia or frank cortical/subcortical small infarcts). Alternatively, ischaemic damage to small arteries and veins could lead to impaired clearance of amyloid and its deposition in vessel walls [15]. There is clearly a need to explore how hypertensive small vessel disease, amyloid angiopathy and AD interact to cause cognitive impairments. CMBs may be particularly interesting in this regard, because they appear to be related to both CAA (in patients with or without AD) and hypertensive small vessel damage.
CMBs are radiological lesions due to small collections of old blood products (in particular, haemosiderin contained within perivascular macrophages) that have previously leaked from cerebral vessels affected by small vessel pathologies ā mainly lipohyaline degeneration (related to hypertension) or amyloid angiopathy [5]. CMBs appear as small, well-demarcated, hypointense, rounded lesions up to about 5ā10Ā mm in diameter on MRI sequences sensitive to their paramagnetic magnetic susceptibility effect ā most commonly gradient-echo T2* sequences. The available evidence suggests that radiologically-defined CMBs are quite specific for perivascular haemosiderin deposits adjacent to small-calibre vessels [5], [16], providing careful attention is paid to avoiding the misclassification of CMB āmimicsā including pial sulcal blood vessels, mineralization (e.g. basal ganglia calcification), or susceptibility effects at air-bone interfaces [5], [17]. Some CMBs have been associated with microaneurysmal or pseudoaneurysmal lesions [18], [19], [20]. CMBs are commonly found in patients with cerebrovascular diseases, including first-ever or recurrent ischaemic or haemorrhagic stroke [21], [22], and in AD and vascular dementia (VaD) defined according to standard criteria [23], [24]. The distribution of CMBs may reflect the underlying type of small vessel disease: it is hypothesized (but not proven) that CMBs in an exclusively deep distribution result from hypertensive arteriopathy, whilst those at the cortico-subcortical boundaries of the cerebral lobes are related to CAA [25]. Thus, CMBs may have promise to detect, quantify and map the effects of small vessel disease and amyloid deposition in patients with cognitive impairment. They may be more specific for the underlying pathology than some other imaging manifestations of small vessel diseases (e.g. WMH), particularly if their anatomical distribution can be mapped [17]. The mechanism(s) by which CMBs might influence cognitive function remain speculative, but could include direct structural damage to surrounding tissue [26], functional disturbances in surrounding tissue, or because of disturbed small vessel reactivity and function.
Section snippets
Studies of cerebral microbleeds and cognition
Please see Table 1 for a summary of studies of the impact of CMBs on cognition in different populations, which are discussed in more detail below.
Future research directions
Much of the previous imaging research has concentrated on one or two MRI manifestations of cerebrovascular disease in isolation, e.g. WMH or lacunes. However, future research should aim to investigate all available imaging markers of cerebrovascular disease together, perhaps in broad clinical cohorts with a range of VCI pathologies (large vessel territorial infarcts, subcortical ischaemic vascular disease, etc.). White matter changes, lacunes, CMBs, as well as cortical infarcts could all be
Conclusions
CMBs are now accepted as a manifestation of cerebral small vessel pathologies, including hypertensive small vessel disease and CAA. CMBs are increasingly detected in normal elderly populations, and in all types of cerebrovascular disease; they are highly prevalent in both VCI and AD. Some studies in VCI, AD and normal individuals have shown a relationship between CMBs and cognition. However, the impact of CMBs on cognitive function in different patient populations remains unclear, and the
Role of funding
David Werring is supported by a Department of Health and Higher Educational and Funding Council for England Clinical Senior Lectureship Award. Simone Gregoire was supported by a grant from The Stroke Association. This work was undertaken at UCLH/UCL who received a proportion of funding from the UK Department of Health's National Institute for Health Research Biomedical Research Centers funding scheme (UCLH/UCL Comprehensive Biomedical Research Trust). The funding sources had no role in any
Conflict of interest
None.
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